PERIPHERAL RETINAL ANGIOGRAPHIC FINDINGS IN MACULAR TELANGIECTASIS TYPE 2.

PURPOSE: To evaluate the retinal periphery in patients with idiopathic juxtafoveal telangiectasis or macular telangiectasis Type 2 (MacTel2), using widefield fluorescein angiography. METHODS: Single-center, retrospective, observational case series of 50 eyes of 50 patients with MacTel2 and 50 eyes of 50 age-matched controls. RESULTS: Thirty-seven eyes in the MacTel2 group (74%) showed peripheral capillary nonperfusion or dropout, compared with 37 eyes in the control group (74%, P = 1.0). Morphologically, the MacTel2 group trended toward having a higher proportion of pruning-type capillary dropout (44%) compared with controls (28%), but this was not statistically significant (P = 0.12). Patients with MacTel2 had a higher incidence of microaneurysms compared with controls (MacTel2 56%; controls 42%; P = 0.048), independent of age or systemic risk factors. There was no difference in the incidence of venous-venous shunts (MacTel2 10%; controls 10%; P = 1.0), arteriovenous shunts (MacTel2 14%; controls 18%; P = 0.60), venous tortuosity (MacTel2 60%; controls 66%; P = 0.58), or arterial tortuosity (MacTel2 54%; controls 68%; P = 0.20), which was mild in most cases. CONCLUSION: We note a high incidence of peripheral vascular and retinal findings in both patients with MacTel2 and age-matched controls, using widefield fluorescein angiography. Patients with MacTel2 had significantly more microaneurysms, independent of age or other systemic risk factors.

CLINICAL OUTCOMES AND TREATMENT COURSE OF EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FOLLOWING THE DEVELOPMENT OF ENDOPHTHALMITIS.

PURPOSE: To evaluate the clinical course of patients with neovascular age-related macular degeneration (nAMD) after developing endophthalmitis during their treatment with intravitreal injections. METHODS: Multicenter, retrospective series. RESULTS: From April 2013 to October 2018, 196,598 intravitreal anti-vascular endothelial growth factor (VEGF) injections were performed, with 75 cases of endophthalmitis (incidence 0.0381%). There was no association between intravitreal anti-VEGF drug (P = 0.29), anesthetic method (P = 0.26), povidone concentration (P = 0.22), or any intraprocedure variable and endophthalmitis incidence. Seventy-two patients (96%) were treated with intravitreal tap and inject , while 3 underwent immediate pars plana vitrectomy. After endophthalmitis resolution, 17 patients (22.7%) were not re-treated for nAMD (in 10 cases due to inactive disease; follow-up, 115 ± 8.4 weeks). Patients required less frequent anti-VEGF injections after infection (7.4 ± 0.61 weeks vs. 11.5 ± 1.8 weeks; P = 0.004). Preinfection logarithm of the minimum angle of resolution visual acuity was 0.585 ± 0.053 (∼20/77). It worsened with endophthalmitis (1.67 ± 0.08, ∼20/935; P < 0.001) and again on postendophthalmitis treatment day 1 (1.94 ± 0.064; count fingers; P < 0.001), but improved after reinitiating nAMD therapy (1.02 ± 0.11; ∼20/209; P < 0.001). Better visual acuity on postendophthalmitis week 1 (P = 0.002) and reinitiation of nAMD treatment (P = 0.008) were associated with better final visual acuity, and streptococcal culture with worse visual acuity (P = 0.028). The postendophthalmitis treatment interval was associated with the anti-VEGF drug used (aflibercept = ranibizumab > bevacizumab; P < 0.001). CONCLUSION: Patients with nAMD required fewer injections after endophthalmitis, suggesting a biological change in disease activity. Neovascular age-related macular degeneration became quiescent in 13.3% of eyes. Most achieved better outcomes with anti-VEGF reinitiation.

ETIOLOGY AND CLINICAL CHARACTERISTICS OF MACULAR EDEMA IN PATIENTS WITH FAMILIAL EXUDATIVE VITREORETINOPATHY.

PURPOSE: To describe the etiology and clinical characteristics of macular edema (ME) in patients with familial exudative vitreoretinopathy. METHODS: Observational, retrospective case series of 30 patients (34 eyes) with ME and familial exudative vitreoretinopathy who underwent spectral-domain optical coherence tomography imaging between 2009 and 2016. Baseline and follow-up optical coherence tomographies were correlated with color fundus photography and fluorescein angiography. RESULTS: The average age was 20.6 years (6.6-68.7). Eighteen eyes exhibited cystoid ME (52.9%), 14 noncystoid ME (41.2%), and 2 eyes (5.9%) with both. Macular edema was foveal in 52.9% (n = 18). Eighteen of 24 eyes (64.3%) with an available fluorescein angiography showed leakage from ME. The most common structural feature was posterior hyaloidal organization/contraction (n = 15). Sixteen eyes were treated with topical or intravitreal steroids (n = 6), intravitreal anti-vascular endothelial growth factor (n = 3), or pars plana vitrectomy with membrane stripping (n = 7). There was no difference between mean preoperative and postoperative LogMAR visual acuity (0.63 [20/85] vs. 0.87 [20/148], P = 0.35) after vitrectomy despite a statistical improvement in the mean central foveal thickness (596 mm vs. 303 mm, P = 0.04). CONCLUSION: Macular edema in familial exudative vitreoretinopathy occurs most commonly because of traction. Vitrectomy is effective for relieving tractional forces with anatomical improvement.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF THE MACULA AND VITREOMACULAR INTERFACE IN PERSISTENT FETAL VASCULATURE SYNDROME WITH POSTERIOR INVOLVEMENT.

PURPOSE: To describe the microstructural features of the macula and vitreomacular interface in persistent fetal vasculature syndrome (PFVS) with posterior involvement managed with early vitrectomy or with observation, with functional correlation. METHODS: We retrospectively identified 45 consecutive pediatric patients with PFVS with posterior involvement treated from 2005 to 2016. The eyes that could be imaged with spectral domain optical coherence tomography were included, and images were correlated with best-corrected visual acuity. RESULTS: Thirty-eight imaging sessions were performed on 10 eyes from 9 patients, including 7 that had been managed with vitrectomy for PFVS-related tractional retinal detachment, and 3 that had been observed. Mean age of the patients who were imaged was 9.1 years and their average length of follow-up was 5.9 years. Best-corrected visual acuities of the eyes imaged ranged from 20/30 to count fingers, with mean best-corrected visual acuity 20/163. All eyes imaged had microstructural anomalies identified. The main anomalous features included posterior hyaloidal organization, vitreoretinal traction, vitreopapillary traction, diminished foveal contour, foveal displacement, and disruption of the ellipsoid zone. Posterior hyaloidal organization (P = 0.043), diminished foveal contour (P = 0.019), and disruption of the ellipsoid zone (P = 0.014) were associated with worse best-corrected visual acuity. CONCLUSION: Macular and vitreomacular interface anomalies were identified in all pediatric patients with posterior PFVS imaged with spectral domain optical coherence tomography. These microstructural findings, together with functional measures, may inform the diagnosis and management of PFVS with posterior involvement.

Long-Term Outcomes of Total Exudative Retinal Detachments in Stage 3B Coats Disease.

PURPOSE: To evaluate the long-term outcomes of treatment of total exudative retinal detachments (ERDs) secondary to Coats disease (stage 3B) and the role of vitrectomy. DESIGN: Retrospective, observational case series. PARTICIPANTS: A total of 16 eyes in 16 patients undergoing treatment for total ERDs secondary to Coats disease with at least 5 years of follow-up. METHODS: We reviewed the records of patients with stage 3B Coats disease. The interventions, including the timing of vitrectomy if used, and clinical course were recorded. MAIN OUTCOME MEASURES: The primary outcome measures were visual acuity at the most recent appointment, whether there was progression to neovascular glaucoma (NVG) or phthisis bulbi, and need for enucleation. RESULTS: All patients received ablative treatment (photocoagulation or cryotherapy), with 8 having scleral buckling (SB) and 6 having external drainage of subretinal fluid (XD). Of the 12 patients who had pars plana vitrectomy (PPV), 8 had early PPV (EV) in the first year after presenting, and 4 of 8 in the expectant management group had late PPV (late vitrectomy) at a mean of 4.3 years post-presentation for treatment of significant traction retinal detachment (TRD). The other 4 patients of 8 in the expectant management group did not require vitrectomy. Mean follow-up overall was 9 1/2 years. At the date of last follow-up, 50% had no light perception or light perception vision, which was consistent across the subgroups that underwent EV (4/8), late vitrectomy (2/4), or no PPV (2/4). A total of 4 of 16 patients had progression to NVG or phthisis, 1 of whom required enucleation. CONCLUSIONS: In this retrospective series of patients with Stage 3B Coats disease, ablative therapy with a combination of PPV, XD, or SB was effective in preventing progression to NVG or phthisis in the majority of patients, thus preserving the globe. Half of the patients (4/8) in this series who did not undergo PPV in the early vitrectomy group developed late-onset TRD, suggesting a possible role for early prophylactic vitrectomy with possible SB and XD; however, this is balanced by the other half (4/8) in the expectant management group who did not require any vitrectomy.

Glaucoma after Lens-Sparing Vitrectomy for Advanced Retinopathy of Prematurity.

PURPOSE: To report the incidence of, and factors related to, glaucoma after lens-sparing vitrectomy (LSV) surgery in advanced retinopathy of prematurity (ROP). DESIGN: Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. PARTICIPANTS: Four hundred and one eyes from 270 patients were included. METHODS: The medical records of patients who underwent LSV for stage 4A, 4B, and 5 ROP were retrospectively reviewed. Data were collected from patient charts including gender, gestational age at birth, birthweight, stage of ROP at presentation, prior treatment (laser or cryotherapy), subsequent retinal surgeries, presence of glaucoma, time to glaucoma (interval between LSV and the onset of glaucoma), date of lensectomy (if performed), and retinal attachment status at last visit. Lensectomy was considered as a time-dependent covariate in the analysis. MAIN OUTCOME MEASURES: Incidence of glaucoma and potential risk factors for time to glaucoma. RESULTS: Among 401 eyes with advanced ROP, 40 eyes (10.0%) had glaucoma during a mean of 3.06±4.11 years of follow-up. The incidence of glaucoma was 6.9% (17/247) in stage 4A, 12.0% (16/133) in stage 4B, and 33.3% (7/21) in stage 5 ROP. Twenty-one percent of eyes (87/401) required lensectomy at a mean of 1.23±2.19 years after LSV. In univariate analysis, having stage 5 ROP (vs. stage 4 ROP) and presence of lensectomy were found to be significantly associated with time to glaucoma (hazard ratio = 6.76, 95% confidence interval = 2.19-20.88, P = 0.001; hazard ratio = 3.06, 95% confidence interval = 1.56-6.0, P = 0.001, respectively). In multivariate analysis, lensectomy was the only significant independent factor associated with time to glaucoma (hazard ratio = 2.76, 95% confidence interval = 1.371-5.581, P = 0.004). CONCLUSIONS: Patients with more severe ROP had a higher incidence of glaucoma after lens-sparing vitrectomy. If a patient required lensectomy owing to progression of ROP and/or presence of lens opacity, then the hazard of having glaucoma significantly increased compared with those without lensectomy.

PROGRESSIVE RETINAL DETACHMENT IN INFANTS WITH RETINOPATHY OF PREMATURITY TREATED WITH INTRAVITREAL BEVACIZUMAB OR RANIBIZUMAB.

PURPOSE: Fibrovascular contraction and tractional retinal detachment (TRD) are recognized complications associated with the use of anti-vascular endothelial growth factor agents in vasoproliferative vitreoretinopathies. The authors characterize TRDs that developed after intravitreal bevacizumab or ranibizumab therapy for vascularly active retinopathy of prematurity. METHODS: This is an international, multicenter, interventional, retrospective, case series. Thirty-five eyes from 23 infants were included. Inclusion required anti-vascular endothelial growth factor treatment of Type 1 retinopathy of prematurity with progression to TRD. RESULTS: Mean gestational age was 26 ± 2 weeks, and mean birth weight was 873 ± 341 g. Mean postmenstrual age on the day of injection was 35 ± 2 weeks. Retinal detachment was noted a mean of 70 days (median, 34; range, 4-335) after injection. Eleven percent detached within 1 week, 23% within 2 weeks, and 49% within 4 weeks. The highest stage of retinopathy of prematurity noted was 4A in 29%, 4B in 37%, and 5 in 34% of eyes. Time to RD negatively correlated with postmenstrual age at the time of injection (Rho = -0.54; P < 0.01). Three TRD configurations were observed: 1) conventional peripheral elevated ridge or volcano-shaped Stage 5 detachment, 2) midperipheral detachment with tight circumferential vectors, and 3) very posterior detachment with prepapillary contraction. Full or partial reattachment was achieved with surgical intervention in 86% of eyes. CONCLUSION: Progressive atypical TRD may occur after anti-vascular endothelial growth factor injections for retinopathy of prematurity. The configuration of the detachment varies with the extent of primary retinal vascularization present at the time of treatment.

THE CUTTING EDGE OF RETINOPATHY OF PREMATURITY CARE: Expanding the Boundaries of Diagnosis and Treatment.

PURPOSE: To discuss the latest advances and controversies in the diagnosis and care of infants with retinopathy of prematurity (ROP). METHODS: Literature review. RESULTS: Retinopathy of prematurity remains a major global issue. Industrialized nations now treat profoundly premature infants with posterior and aggressive disease, and middle-income nations are experiencing ROP epidemics. Remote digital imaging may address the decreasing ratio of ROP providers to premature infants, in addition to improving patient care. Widefield angiography, optical coherence tomography, and the Wnt signaling pathway have provided new insights into ROP pathogenesis. Anti-vascular endothelial growth factor treatment is increasing in popularity, but the dearth of information to guide dosing, unpredictable reactivation, persistent vascular abnormalities, the "crunch" phenomenon, and the presently unknown effects of systemic vascular endothelial growth factor suppression remain issues to continue investigating. Neurodevelopmental delay has been raised as a potential consequence, but the evidence currently is weak. Vitrectomy is the treatment of choice for Stages 4 and 5. Illumination techniques, ab interno incisions, plasmin-assisted vitrectomy, staged surgery in the interest of corneal clearing for advanced Stage 5, and immediate sequential bilateral vitreoretinal surgery, are useful techniques. CONCLUSION: We are making progress in ROP management. Our goal as clinicians is to continue expanding the boundaries of our abilities to keep this blinding disease in check globally.

Evaluation of Screening for Retinopathy of Prematurity by ROPtool or a Lay Reader.

PURPOSE: To determine if (1) tortuosity assessment by a computer program (ROPtool, developed at the University of North Carolina, Chapel Hill, and Duke University, and licensed by FocusROP) that traces retinal blood vessels and (2) assessment by a lay reader are comparable with assessment by a panel of 3 retinopathy of prematurity (ROP) experts for remote clinical grading of vascular abnormalities such as plus disease. DESIGN: Validity and reliability analysis of diagnostic tools. PARTICIPANTS: Three hundred thirty-five fundus images of prematurely born infants. METHODS: Three hundred thirty-five fundus images of prematurely born infants were obtained by neonatal intensive care unit nurses. A panel of 3 ROP experts graded 84 images showing vascular dilatation, tortuosity, or both and 251 images showing no evidence of vascular abnormalities. These images were sent electronically to an experienced lay reader who independently graded them for vascular abnormalities. The images also were analyzed using the ROPtool, which assigns a numerical value to the level of vascular abnormality and tortuosity present in each of 4 quadrants or sectors. The ROPtool measurements of vascular abnormalities were graded and compared with expert panel grades with a receiver operating characteristic (ROC) curve. Grades between human readers were cross-tabulated. The area under the ROC curve was calculated for the ROPtool, and sensitivity and specificity were computed for the lay reader. MAIN OUTCOME MEASURES: Measurements of vascular abnormalities by ROPtool and grading of vascular abnormalities by 3 ROP experts and 1 experienced lay reader. RESULTS: The ROC curve for ROPtool's tortuosity assessment had an area under the ROC curve of 0.917. Using a threshold value of 4.97 for the second most tortuous quadrant, ROPtool's sensitivity was 91% and its specificity was 82%. Lay reader sensitivity and specificity were 99% and 73%, respectively, and had high reliability (κ, 0.87) in repeated measurements. CONCLUSIONS: ROPtool had very good accuracy for detection of vascular abnormalities suggestive of plus disease when compared with expert physician graders. The lay reader's results showed excellent sensitivity and good specificity when compared with those of the expert graders. These options for remote reading of images to detect vascular abnormalities deserve consideration in the quest to use telemedicine with remote reading for efficient delivery of high-quality care and to detect infants requiring bedside examination.

Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study.

PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.

WIDE-FIELD IMAGING OF NONEXUDATIVE AND EXUDATIVE CONGENITAL X-LINKED RETINOSCHISIS.

PURPOSE: To describe wide-field imaging features of patients with congenital X-linked retinoschisis. METHODS: This is a retrospective nonconsecutive series of 36 eyes from 18 patients with congenital X-linked retinoschisis from 2008 to 2014. Wide-field color fundus photographs, optical coherence tomography images, and wide-field fluorescein angiography images were reviewed. Patients were classified to have either exudative or nonexudative retinoschisis based on the presence or absence of lipid exudates. RESULTS: Eleven eyes exhibited exudative retinoschisis (30%), whereas the remaining were nonexudative. Exudative disease occurred more commonly in older patients (14.4 vs. 4.0 years; P < 0.001). The most frequent location of exudation was the macula. Subretinal hemorrhage was present in 4 eyes (11%). Macular findings included an atypical foveal avascular zone in 7 eyes (19%) and submacular fibrosis or retinal folds in 6 eyes (17%). Peripheral characteristics included fibrosis or folds (11%), bridging vessels (8%), and vascular sheathing (8%). Thirteen of the 22 eyes (59%) demonstrated leakage on fluorescein angiography. CONCLUSION: Exudation may be more common in congenital X-linked retinoschisis than previously recognized. The presence of exudates with concurrent angiographic leakage suggests that exudation may be due to chronic vascular permeability and not solely caused by intraschisis hemorrhage, which has been classically described.

WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN PATIENTS WITHOUT PERIPHERAL DISEASE: A Study of Normal Peripheral Findings.

PURPOSE: Widefield photography and angiography provide access up to 200-degrees of the retinal periphery. The range of normal peripheral findings has not been characterized, yet is relevant to studies addressing putative peripheral retinal vascular pathology. METHODS: This study was an observational retrospective cohort study. Adult patients with epiretinal membrane or choroidal nevi who underwent imaging with Optos 200 MA/200Tx were included. Dye transit times, peripheral arteriovenous shunting, presence of vessels crossing the horizontal raphe, right angle vessels, terminal networks, absence of capillary detail, ground glass hyperfluorescence, peripheral drusen, and microaneurysms were evaluated. RESULTS: Fifty-eight eyes of 31 patients met inclusion criteria. Mean peripheral arterial filling time was 8.65 ± 2.54 seconds (range 3-15 seconds). One or more peripheral anomalies were noted in all patients (P < 0.01). The prevalences of findings were: arteriovenous shunting (0.00%), vessels crossing the horizontal raphe (44.83%), right angle vessels (70.69%), terminal networks (77.59%), absence of capillary detail (98.28%), ground glass hyperfluorescence (87.93%), drusen (34.48%), and microaneurysms (41.38%). CONCLUSION: There was a high prevalence of peripheral vascular anatomic variations in eyes expected to have normal peripheral retinal vasculature. These findings may provide a reference for future studies addressing putative pathologic peripheral angiographic findings.

Familial Exudative Vitreoretinopathy: Spectral-Domain Optical Coherence Tomography of the Vitreoretinal Interface, Retina, and Choroid.

PURPOSE: The in vivo microstructural features of familial exudative vitreoretinopathy (FEVR) have not been well described. We present new anatomic features of FEVR with functional and genetic correlations. DESIGN: Consecutive, retrospective, observational case series. PARTICIPANTS: Patients with FEVR treated from 2009 to 2014. METHODS: We identified 346 patients with FEVR. Those imaged with spectral-domain optical coherence tomography (SD OCT) with or without enhanced depth imaging (EDI) were included, and images were correlated with best-corrected visual acuity (BCVA), widefield angiography, fundus autofluorescence (AF), and wnt signaling pathway mutations. MAIN OUTCOME MEASURES: Exploratory SD OCT findings and BCVA. RESULTS: A total of 225 imaging sessions were acquired in 74 eyes from 41 patients. Mean age was 19.0 years. Sixty-seven eyes (91%) had interpretable images, of which 50 (75%) had anomalous microstructural findings; all eyes with FEVR severity of stage 2 or greater had abnormalities. A broad spectrum of features were identified: various forms of posterior hyaloidal organization, vitreomacular traction (VMT), vitreopapillary traction, vitreo-fold traction, vitreo-laser scar adhesion, diminished foveal contour, persistent fetal foveal architecture, cystoid macular edema (CME), intraretinal exudates and subretinal lipid aggregation, dry or edematous radial folds, and disruption of the ellipsoid zone. Mean foveal, central macular, and choroidal thicknesses were 305±145 µm, 337±160 µm, and 216±64 µm, respectively. In stages 1 to 2, greater foveal and central macular thicknesses (Rho=0.493, 0.544, respectively; both P<0.001) correlated with poorer BCVA, but not choroidal thickness (Rho=0.032; P=0.868). Posterior hyaloidal organization (P<0.001), VMT (P<0.001), CME (P<0.001), exudation (P<0.001), and disruption of the ellipsoid zone (P<0.001) were associated with poorer BCVA. Disruption of the ellipsoid zone (ß=0.699; P<0.001) and posterior hyaloidal organization (ß=0.289; P=0.011) retained significance in multivariate modeling (R2=0.627; P<0.001). Spectral-domain OCT detected all cases of angiographic edema and areas of outer retinal dysfunction that were hypoautofluorescent on AF. Microstructural-genetic associations were not identified. CONCLUSIONS: Spectral-domain OCT imaging identified microstructural anomalies in the majority of patients with FEVR.

Long-term outcomes on lens clarity after lens-sparing vitrectomy for retinopathy of prematurity.

OBJECTIVE: To describe the long-term effect of lens-sparing vitrectomy surgery for advanced retinopathy of prematurity (ROP) on lens clarity. DESIGN: Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. PARTICIPANTS: Four hundred ninety-six eyes from 351 patients were included. METHODS: A retrospective chart review was conducted of patients with diagnosis of ROP stage 4A, 4B, and 5 who underwent lens-sparing vitrectomy (LSV) between 1992 and 2013. Data were collected from patient charts, including gender, date of birth, gestational age at birth, birthweight, stage of ROP at presentation, initial treatment (laser or cryotherapy), date of LSV, date of lensectomy (if performed), lens status at time of lensectomy, date of last visit, lens status at last visit, subsequent retinal surgeries, and retinal attachment status at last visit. Patients were excluded if any surgery had been performed at an outside institution before referral, or if a scleral buckle had been placed. Eyes with a concurrent anatomic abnormality, such as coloboma or microcornea, or a known family history of familial exudative vitreoretinopathy (FEVR), were also excluded. MAIN OUTCOME MEASURES: Retinal reattachment after LSV, lensectomy after LSV, lens opacity at the time of lensectomy, and lens clarity at last follow-up. RESULTS: Four hundred ninety-six eyes from 351 patients met inclusion criteria for this study. The reattachment rate after a single LSV surgery was 82.1% for stage 4A, 69.5% for stage 4B, and 42.6% for stage 5. Subsequent retinal surgeries were required in 19.8% of eyes, with 88.7% of them including a lensectomy. Among eyes requiring lensectomy, 75% occurred within the first year after LSV surgery. Lens opacities were present in 26.6% of eyes at the time of lensectomy. Of all eyes in this series, 5.9% required lensectomy because of lens opacity. CONCLUSIONS: This study demonstrates that lens clarity is observed in most eyes after LSV surgery for advanced ROP for the patient's childhood. Within the first decade of life, if necessary, lensectomy after LSV occurred mostly within 1 year following LSV.

High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy.

OBJECTIVE: To describe the prevalence and severity of familial exudative vitreoretinopathy (FEVR) in asymptomatic relatives of known symptomatic FEVR patients. DESIGN: Uncontrolled and retrospective case series at a single tertiary referral vitreoretinal practice. PARTICIPANTS: A total of 148 eyes of 74 subjects were studied. METHODS: A retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included confirmed clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a definitive diagnosis of FEVR could not be made. MAIN OUTCOME MEASURES: Clinical and angiographic findings. RESULTS: A total of 74 subjects from 17 separate families met the inclusion criteria for this study. There were an average of 4.4 subjects per family included in this study. The cohort was 55% male and included 17 patients and 57 family members who agreed to undergo genotyping, examination, and diagnostic imaging. Forty-three percent of FEVR patients had detectable mutations in FZD4, NDP, or TSPAN12. Only 8% of the cohort reported a positive family history of FEVR in a first-degree relative. Among the index patients, 76% had clinical stage 3, 4, or 5 FEVR and 24% had stage 1 or 2 FEVR. Among the asymptomatic family members screened, 58% demonstrated clinical or angiographic findings consistent with stage 1 or 2 FEVR and 21% demonstrated clinical or angiographic findings consistent with stage 3, 4, or 5 FEVR. CONCLUSIONS: Asymptomatic family members of FEVR patients frequently have early manifestations of FEVR (stage 1 or 2). Early-stage FEVR may progress to more advanced stages, which can result in vision loss. These data support the use of angiographic screening and clinical examination in immediate relatives of patients with symptomatic FEVR.

Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy.

PURPOSE: To describe the diversity of clinical findings associated with familial exudative vitreoretinopathy (FEVR) using wide-field angiography and to update the current classification system. DESIGN: Retrospective case series at a single tertiary referral vitreoretinal practice. PARTICIPANTS: A total of 174 eyes of 87 subjects were studied. METHODS: A retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a diagnosis of FEVR could not be made. MAIN OUTCOME MEASURES: Clinical and angiographic findings. RESULTS: A total of 87 subjects met the inclusion criteria for this study. A broad spectrum of previously undescribed clinical and angiographic findings were associated with FEVR on wide-field angiography. These findings can be grossly divided into anatomic and functional changes. Anatomic changes include aberrant circumferential peripheral vessels, venous and arterial tortuosity, late-phase disc leakage, central and peripheral telangiectasias, capillary anomalies, and capillary agenesis. Functional changes include venous-venous shunting, delayed arteriovenous transit, and delayed or absent choroidal perfusion on fluorescein angiography. CONCLUSIONS: Familial exudative vitreoretinopathy has a wide range of unrecognized or under-recognized clinical and angiographic findings that are easily identified using wide-field fluorescein angiography. These novel findings have led to an update of the original FEVR classification scheme and more complete characterization of early stages of FEVR.

Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13-12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13-23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in FZD4, encoding the putative Wnt receptor frizzled-4, segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca(2+) signaling pathway. In one of the mutants, altered subcellular trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.

Late Vitreoretinal Complications of Regressed Retinopathy of Prematurity: Retinal Break, Vitreous Hemorrhage, and Retinal Detachment.

PURPOSE: To investigate late vitreoretinal complications and visual outcomes in patients with regressed retinopathy of prematurity (ROP) with or without prior treatment. DESIGN: International, multicenter, noncomparative retrospective case series. PARTICIPANTS: We analyzed 264 eyes of 238 patients from 13 centers worldwide who developed vitreoretinal complications (retinal detachment [RD], vitreous hemorrhage [VH], or retinal break) ≥ 2 years after resolution of acute ROP. METHODS: Each participant was assigned to 1 of 3 groups (the RD, VH, and retinal break groups) according to their primary diagnosis. The average age at presentation, visual acuities, refractive error, axial length, gestational age, birth weight, acute ROP classification, prior treatments for acute ROP, postoperative visual acuity (VA), and concomitant eye conditions in the 3 groups were documented and compared. MAIN OUTCOME MEASURES: Clinical features and visual outcomes of late vitreoretinal complications in patients with regressed ROP. RESULTS: A total of 264 eyes of 238 patients were included. The prior acute ROP status was comparable among the 3 groups, except that the VH group had a higher proportion of patients with type 1 ROP (P = 0.03) and prior treatment (P < 0.001) than the other groups. The average age at presentation was earlier in the RD (20.3 ± 15.5 years) and VH (21.4 ± 18.9 years) groups than in the retinal break group (31.9 ± 18.2 years; P < 0.001). The retinal break group had the best presenting best-corrected VA, followed by the RD and VH groups (P < 0.001). Surgical intervention improved VA in both the RD and VH groups (both P < 0.05). The overall trend of VA was the most favorable in the retinal break group, followed by that in the VH and RD groups. Cicatricial changes in the fellow retina were observed in > 90% of patients with unilateral involvement. CONCLUSIONS: Infants with acute ROP remain at a high risk of vision-threatening complications throughout childhood and adulthood. Continual follow-up of patients with ROP is important. When severe complications, such as RD or VH, are detected, timely surgical intervention is necessary to ensure favorable visual outcomes in these patients.